A clue about ethidium toxicity

[David F. Spencer]

Undergrad wrote:
> As you know ethidium (aka homidium) is also used as trypanocide in cattle,
> sheep, goat ect... No ADI (admitted daily intake) are available for ethidium
> however there is one for isometamidium which is a closely related to
> homidium and also intercalate in DNA. Also it was found that isometamidium
> is transform in homidium in the body (less thant
> 1%)(http://www.inchem.org/documents/jecfa/jecmono/v31je10.htm).
> 
> 
> The ADI of isometamidium is 0-100 microgramme/kg
> (http://66.102.9.104/search?q=cache:7ct_Z9QkXWwJ:www.ipfsaph.org/cds_static/en/jecfa_veterinary_drug_residue_isometamidium_en_cthttpwwwfaoorgaosipfsaphinformat
> ionsourcejecfa_JECFAEVAL57.html+isometamidium+who+adi&hl=en&ct=clnk&cd=1&gl=uk).
> 
> 
> "
> An ADI of 0-100 µg per kg of body-weight was established for
> isometamidium based on the non-toxic dose level of 50 mg/kg bw/day
> in the 13-week rat study and a safety factor of 500. The Committee
> chose this safety factor because of the marginal pharmacological
> effects seen at the lowest dose in the rat study and the limited
> extent of the data available, although it recognized that neither
> the drug nor its metabolites were bioavailable when given by the
> oral route."
> 
> 
> So if isomethidium give rise to 0.1% of homidium, the proportionnal ADI of
> homidium could be : 0.1 microgramme par kg so 6 microgramme for a 60 kg
> person. 
> 
> In this study, it is shown that isometamidium have a strongest toxic effect
> than homidium: http://www.inchem.org/documents/jecfa/jecmono/v25je10.htm  
>     
> 

If you search through the archives of this newsgroup (which I think are 
still accessible?) you will find previous discussions of this topic, 
including at least one rant of mine.

Isometamidium chloride is a derivative of ethidium/homidium but larger 
and I suspect that the presence of the azo (-N=N-) moiety (which is 
actually triazo because it is Ar-N-N=N-Ar may make the comparison to 
homidium incorrect because isometamidium is probably chemically reactive 
(which ethidium is not). Although both molecules contain conjugated 
aromatic rings (which makes them interculating agents) they are also 
ions (by virtue of having a quaternary nitrogen) and consequently will 
not pass readily through undamaged cell membranes. To actually suffer 
mutagenic/carcinogenic effects from ethidium bromide it would have to 
get access to exposed replicating DNA and in complex multicellular 
animals the chances of that would be extremely remote.

Dave Spencer